Human coronaviruses (HCoVs) are positive-stranded RNA viruses that are estimated to account for approximately 30% of cases of the common cold. The emergence of a novel HCoV as the etiologic agent of severe acute respiratory syndrome (SARS) demonstrated the potential of coronaviruses to induce severe respiratory disease and cause a significant impact human heath. Although SARS-CoV has not re-emerged within the human population since its initial outbreak, the recent isolation of related coronaviruses from natural mammalian reservoirs such as bats suggest that animal-to-human transmission of a virulent coronavirus may occur again in the future. A more complete understanding of the immune response in the respiratory tract following pulmonary coronavirus infection would enhance our ability to effectively treat future outbreaks of emerging coronavirus infections. Animal models are critical to understanding the pathogenesis of human coronavirus infections and are important for evaluating the efficacy of vaccines and other potential immune interventions. Intranasal mouse hepatitis virus strain 1 (MHV-1) infection of C3H mice produces an acute respiratory disease with a high lethality rate that shares several pathological similarities with human SARS cases. C3H/HeJ mice that harbor a natural mutation in the gene that encodes toll-like receptor 4 (TLR4) that disrupts its normal function, exhibit greatly increased morbidity and mortality after intranasal MHV-1 infection as compared to wild-type controls. In contrast to susceptible C3H mice, C57BL/6 mice do not develop disease following intranasal MHV-1 infection. However, MHV-1 infection of type I IFN receptor-deficient mice on the C57BL/6 background results in uncontrolled virus replication in multiple tissues demonstrating the important role for innate immunity and type I IFN in mediating the early control of MHV-1 infection. Taken together these data indicate that innate immunity plays a crucial role in the early control of respiratory coronavirus infection, however the host sensor pathways responsible for the early induction of the innate immune response to coronaviruses in vivo are currently poorly understood. The overall goal of this proposal is to define how the innate immune response influences the development of the subsequent adaptive immune response to pulmonary coronavirus infections. This proposal will examine the following Specific Aims: 1) determine the why TLR4 deficiency results in enhanced mortality after intranasal MHV-1 infection of C3H mice and 2) determine which host pathogen recognition receptors recognize intranasal MHV-1 infection in resistant C57BL/6 mice. The knowledge gained from this study will provide a better understanding of the early events required for effective control of coronavirus infection and also provide novel approaches for the therapeutic intervention of respiratory coronavirus infections. Human coronaviruses cause respiratory tract infections in humans that can result in mild disease similar to the common cold as well as potentially fatal cases of severe respiratory disease. The overall goal of this proposal is to define how the initial innate immune response influences the development of the subsequent adaptive immune response to pulmonary coronavirus infections. This information will provide novel approaches for therapeutic intervention of respiratory coronavirus infections and aid in the design of future coronavirus vaccines.